Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, 200438, China.
Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, 46000, Pakistan.
Mol Genet Genomics. 2024 Sep 2;299(1):84. doi: 10.1007/s00438-024-02168-9.
Male infertility is a complex multifactorial reproductive disorder with highly heterogeneous phenotypic presentations. Azoospermia is a medically non-manageable cause of male infertility affecting ∼1% of men. Precise etiology of azoospermia is not known in approximately three-fourth of the cases. To explore the genetic basis of azoospermia, we performed whole exome sequencing in two non-obstructive azoospermia affected siblings from a consanguineous Pakistani family. Bioinformatic filtering and segregation analysis of whole exome sequencing data resulted in the identification of a rare homozygous missense variant (c.962G>C, p. Arg321Thr) in YTHDC2, segregating with disease in the family. Structural analysis of the missense variant identified in our study and two previously reported functionally characterized missense changes (p. Glu332Gln and p. His327Arg) in mice showed that all these three variants may affect Mg binding ability and helicase activity of YTHDC2. Collectively, our genetic analyses and experimental observations revealed that missense variant of YTHDC2 can induce azoospermia in humans. These findings indicate the important role of YTHDC2 deficiency for azoospermia and will provide important guidance for genetic counseling of male infertility.
男性不育是一种复杂的多因素生殖障碍，具有高度异质的表型表现。无精子症是一种医学上无法治疗的男性不育原因，影响约 1%的男性。大约四分之三的无精子症病例的精确病因尚不清楚。为了探索无精子症的遗传基础，我们对来自一个巴基斯坦近亲家庭的两名非梗阻性无精子症受影响的兄弟姐妹进行了全外显子组测序。全外显子组测序数据的生物信息学过滤和分离分析导致鉴定出 YTHDC2 中的一个罕见纯合错义变异（c.962G>C，p.Arg321Thr），该变异在家族中与疾病共分离。我们在研究中发现的错义变异以及之前在小鼠中报道的两种具有功能特征的错义变化（p.Glu332Gln 和 p.His327Arg）的结构分析表明，所有这三种变异都可能影响 YTHDC2 的 Mg 结合能力和解旋酶活性。总之，我们的遗传分析和实验观察表明，YTHDC2 的错义变异可导致人类无精子症。这些发现表明 YTHDC2 缺陷对无精子症的重要作用，并将为男性不育的遗传咨询提供重要指导。
